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Advanced Neurology LLPS in neurodegenerative diseases

condensates, how disease-related mutations or Ethics approval and consent to participate
epigenetic modifications affect the physical properties of
condensates, and how LLPS can be regulated to achieve Not applicable.
the desired effect in the treatment of neurodegenerative Consent for publication
diseases. Currently, there is no universally accepted
definitive test or “gold standard” for conclusively Not applicable.
confirming that a process is driven by LLPS, and some Availability of data
methods for visualizing LLPS in vitro are prone to
artifacts. 98-100 The use of high concentrations of in vitro Not applicable.
is particularly problematic as many proteins will form
LLPS in the presence of crowders at unphysiologically References
high concentrations. 101,102 Some molecular behaviors, 1. Zhang H, Ji X, Li P, et al. Liquid-liquid phase separation in
such as short-lived, non-specific binding interactions, biology: Mechanisms, physiological functions and human
can also produce effects that appear like LLPS but arise diseases. Sci China Life Sci. 2020;63(7):953-985.
from physical mechanisms that are inherently different in doi: 10.1007/s11427-020-1702-x
nature. Still, the phase state of water inside and outside
98
the cell is controversial. The experimental conditions 2. Elbaum-Garfinkle S, Kim Y, Szczepaniak K, et al. The
103
disordered P granule protein LAF-1 drives phase separation
in the current study are highly biased and do not exactly into droplets with tunable viscosity and dynamics. Proc Natl
match the physiological conditions. Therefore, the Acad Sci U S A. 2015;112(23):7189-7194.
conclusions drawn from these studies may not be fully
consistent with the function of in vivo phase separation. doi: 10.1073/pnas.1504822112
Further methods and tools for LLPS research should be 3. Alberti S, Hyman AA. Biomolecular condensates at the
developed in the future. nexus of cellular stress, protein aggregation disease and
ageing. Nat Rev Mol Cell Biol. 2021;22(3):196-213.
Acknowledgments doi: 10.1038/s41580-020-00326-6
None. 4. Banani SF, Lee HO, Hyman AA, Rosen MK. Biomolecular
condensates: Organizers of cellular biochemistry. Nat Rev
Funding Mol Cell Biol. 2017;18(5):285-298.
This work was supported by grants from the National doi: 10.1038/nrm.2017.7
Natural Science Foundation of China (Grant Numbers: 5. Gao C, Gu J, Zhang H, et al. Hyperosmotic-stress-induced
82171193, 81930035, 82230048, 92249303, and 91749208), liquid-liquid phase separation of ALS-related proteins in the
the National Key R&D Program of China (Grant Number: nucleus. Cell Rep. 2022;40(3):111086.
2018YFC2001901), Jiangsu Provincial Medical Key
Discipline (Grant Number: ZDXK202232), and the Qing doi: 10.1016/j.celrep.2022.111086
Lan Project. 6. Wang B, Zhang L, Dai T, et al. Liquid-liquid phase separation
in human health and diseases. Signal Transduct Target Ther.
Conflict of interest 2021;6(1):290.

Xiaoping Gu is an Editorial Board Member of this journal doi: 10.1038/s41392-021-00678-1
but was not in any way involved in the editorial and 7. Hayashi Y, Ford LK, Fioriti L, McGurk L, Zhang M. Liquid-
peer-review process conducted for this paper, directly or liquid phase separation in physiology and pathophysiology
indirectly. Separately, other authors declared that they of the nervous system. J Neurosci. 2021;41(5):834-844.
have no known competing financial interests or personal doi: 10.1523/jneurosci.1656-20.2020
relationships that could have influenced the work reported
in this paper. 8. Mathieu C, Pappu RV, Taylor JP. Beyond aggregation:
Pathological phase transitions in neurodegenerative disease.
Author contributions Science. 2020;370(6512):56-60.
doi: 10.1126/science.abb8032
Conceptualization: Yiming Zhou, Cihang Liu, Tianjiao Xia
Writing – original draft: Yiming Zhou, Xinlu Chen, 9. Zbinden A, Pérez-Berlanga M, De Rossi P, Polymenidou M.
Ying Wang Phase separation and neurodegenerative diseases:
Writing – review & editing: Yiming Zhou, Cihang Liu, A disturbance in the force. Dev Cell. 2020;55(1):45-68.
Tianjiao Xia, Xiaoping Gu doi: 10.1016/j.devcel.2020.09.014

Volume 4 Issue 1 (2025) 47 doi: 10.36922/an.4493